Synapse - Tumorigenesis driven by BRAF(V600E) requires secondary mutations that overcome its feedback inhibition of RAC1 and migration

Tumorigenesis driven by BRAF(V600E) requires secondary mutations that overcome its feedback inhibition of RAC1 and migration Journal Article

Authors:	Gadal, S.; Boyer, J. A.; Roy, S. F.; Outmezguine, N. A.; Sharma, M.; Li, H.; Fan, N.; Chan, E.; Romin, Y.; Barlas, A.; Chang, Q.; Pancholi, P.; Timaul, N. M.; Overholtzer, M.; Yaeger, R.; Manova-Todorova, K.; de Stanchina, E.; Bosenberg, M. W.; Rosen, N.
Article Title:	Tumorigenesis driven by BRAF(V600E) requires secondary mutations that overcome its feedback inhibition of RAC1 and migration
Abstract:	BRAFV600E mutations occur in 46% of melanomas and drive high levels of ERK activity and ERK-dependent proliferation. However, BRAFV600E is insufficient to drive melanoma in genetically engineered mouse models, and 82% of human benign nevi harbor BRAFV600E mutations. We found that BRAFV600E inhibited mesenchymal migration by causing feedback inhibition of RAC1 activity. ERK pathway inhibition induced RAC1 activation and restored migration and invasion. In cells with BRAFV600E, mutant RAC1 or PTEN inactivation restored RAC1 activity and cell motility. Together, these lesions occurred in 26% of melanomas with BRAFV600E mutations. Thus, although BRAFV600E activation of ERK deregulates cell proliferation, it prevents full malignant transformation by causing feedback inhibition of RAC1. Secondary mutations are, therefore, required for tumorigenesis. One mechanism underlying tumor evolution may be the selection of lesions that rescue the deleterious effects of oncogenic drivers. ©2025 The Authors;
Keywords:	controlled study; gene mutation; human cell; genetics; mutation; histopathology; nonhuman; cell proliferation; mouse; animal; metabolism; animals; mice; animal tissue; melanoma; map kinase signaling system; confocal microscopy; skin neoplasms; tumor volume; animal experiment; animal model; cell motion; immunofluorescence; pathology; cell line, tumor; carcinogenesis; cell transformation, neoplastic; extracellular matrix; skin tumor; tumor cell line; immunoblotting; cell migration; cell movement; down regulation; negative feedback; feedback, physiological; cell invasion; b raf kinase; proto-oncogene proteins b-raf; braf protein, human; braf protein, mouse; rac1 protein; bright field microscopy; vemurafenib; rac1 gtp-binding protein; trametinib; mapk signaling; dna transfection; n [3 (5 chloro 1h pyrrolo[2,3 b]pyridine 3 carbonyl) 2,4 difluorophenyl]propanesulfonamide; humans; human; female; article; masitinib; cell migration assay; pexidartinib; cell invasion assay; transwell assay; wound healing assay; physiological feedback; pull-down assay; neoplastic cell transformation; amuvatinib; rac1 protein, human
Journal Title:	Cancer Research
Volume:	85
Issue:	9
ISSN:	0008-5472
Publisher:	American Association for Cancer Research
Date Published:	2025-05-01
Start Page:	1611
End Page:	1627
Language:	English
DOI:	10.1158/0008-5472.Can-24-2220
PUBMED:	39992718
PROVIDER:	scopus
PMCID:	PMC12046322
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-105004567867&doi=10.1158%2f0008-5472.CAN-24-2220&partnerID=40&md5=c904af449f50514892d9dfde31be896a
Notes:	Article -- Source: Scopus